COVID-19 Thrombotic Complications and Therapeutic Strategies.

Shortly after the emergence of coronavirus disease 2019 (COVID-19) in late 2019, clinicians rapidly recognized an apparent association between the disease and both arterial and venous thrombotic complications, which was confirmed in epidemiologic studies. Based on these data, hospitals empirically developed and implemented protocols with different strategies for anticoagulation of hospitalized COVID-19 patients. Subsequent randomized controlled trials (RCTs) clarified the role of anticoagulation in patients hospitalized with COVID-19 and recently discharged from the hospital. In this review, we discuss the epidemiology and pathophysiology of thrombosis in patients with COVID-19, observational comparative effectiveness analyses that provided hints of a benefit from anticoagulation, and finally the RCTs that established which patients with COVID-19 benefit from treatment-dose anticoagulation. These RCTs have demonstrated that hospitalized, noncritically ill patients with COVID-19 benefit from treatment-dose anticoagulation, but patients who are hospitalized and critically ill, discharged from the hospital, or not hospitalized do not benefit.

Aspirin Versus Clopidogrel for Long-Term Maintenance Monotherapy After Percutaneous Coronary Intervention: The HOST-EXAM Extended Study.

BACKGROUND: Long-term outcomes of antiplatelet monotherapy in patients who receive percutaneous coronary intervention are unknown. The HOST-EXAM (Harmonizing Optimal Strategy for Treatment of Coronary Artery Stenosis-Extended Antiplatelet Monotherapy) Extended study reports the posttrial follow-up results of the original HOST-EXAM trial. METHODS: From March 2014 through May 2018, 5438 patients who maintained dual antiplatelet therapy without clinical events for 12±6 months after percutaneous coronary intervention with drug-eluting stents were randomly assigned in a 1:1 ratio to receive clopidogrel (75 mg once daily) or aspirin (100 mg once daily). The primary end point (a composite of all-cause death, nonfatal myocardial infarction, stroke, readmission attributable to acute coronary syndrome, and Bleeding Academic Research Consortium type 3 or greater bleeding), secondary thrombotic end point (cardiac death, nonfatal myocardial infarction, ischemic stroke, readmission attributable to acute coronary syndrome, and definite or probable stent thrombosis), and bleeding end point (Bleeding Academic Research Consortium type 2 or greater bleeding) were analyzed during the extended follow-up period. Analysis was performed on the per-protocol population (2431 patients in the clopidogrel group and 2286 patients in the aspirin group). RESULTS: During a median follow-up of 5.8 years (interquartile range, 4.8-6.2 years), the primary end point occurred in 12.8% and 16.9% in the clopidogrel and aspirin groups, respectively (hazard ratio, 0.74 [95% CI, 0.63-0.86]; P<0.001). The clopidogrel group had a lower risk for the secondary thrombotic end point (7.9% versus 11.9%; hazard ratio, 0.66 [95% CI, 0.55-0.79]; P<0.001) and secondary bleeding end point (4.5% versus 6.1%; hazard ratio, 0.74 [95% CI, 0.57-0.94]; P=0.016). There was no significant difference in the incidence of all-cause death between the 2 groups (6.2% versus 6.0%; hazard ratio, 1.04 [95% CI, 0.82-1.31]; P=0.742). Landmark analysis at 2 years showed that the beneficial effect of clopidogrel was consistent throughout the follow-up period. CONCLUSIONS: During an extended follow-up of >5 years after randomization, clopidogrel monotherapy compared with aspirin monotherapy was associated with lower rates of the composite net clinical outcome in patients without clinical events for 12±6 months after percutaneous coronary intervention with drug-eluting stents. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT02044250.

Dual Antiplatelet Therapy After Embolic Stroke of Undetermined Source: A Subgroup Analysis of the CHANCE-2 Trial.

BACKGROUND: The atherosclerotic sources of embolism are a significant contributor to embolic stroke of undetermined source (ESUS). However, there is limited evidence for the efficacy of intensive dual antiplatelet therapy for ESUS. We conducted an investigation to determine whether gene-directed dual antiplatelet therapy could reduce the risk of recurrent stroke in patients with ESUS. METHODS: CHANCE-2 (Clopidogrel in High-Risk Patients with Acute Nondisabling Cerebrovascular Events-II) was an investigator-initiated, multicenter, randomized, double-blind, placebo-controlled trial that objectively compared ticagrelor plus aspirin and clopidogrel plus aspirin in patients with minor stroke or transient ischemic attack who carried CYP2C19 loss-of-function alleles in China. All study participants were classified into ESUS and non-ESUS groups for the prespecified exploratory analysis. Cox proportional hazards models were used to assess the interaction of the state of ESUS with the effects of dual antiplatelet therapy with ticagrelor-aspirin versus clopidogrel-aspirin, adjusting for sociodemographic and clinical factors. RESULTS: The subgroup analysis comprised 5796 participants (90.4% of the total 6412 participants) in the CHANCE-2 trial, with a median age of 64.9 years (range, 57.0-71.4 years), of whom 1964 (33.9%) were female. These participants underwent diffusion-weighted imaging as part of the study protocol. After systematic evaluation, 15.2% of patients (881/5796) were deemed to have ESUS. The incidence of stroke recurrence in patients with ESUS was found to be 5.6% in the ticagrelor-aspirin group and 9.2% in the clopidogrel-aspirin group (hazard ratio, 0.57 [95% CI, 0.33-0.99]; P=0.04). In patients without ESUS, the respective incidence rates were 5.6% and 7.5% (hazard ratio, 0.72 [95% CI, 0.58-0.90]; P<0.01). The P value was 0.56 for the treatment × ESUS status interaction effect. CONCLUSIONS: In this prespecified exploratory analysis, ticagrelor with aspirin was superior to clopidogrel with aspirin for preventing stroke at 90 days in patients with acute ischemic stroke or transient ischemic attack who carried CYP2C19 loss-of-function alleles and were classified as ESUS. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04078737.

Transcranial Doppler With Microbubbles: Screening Test to Detect and Grade Right-to-Left Shunt After an Ischemic Stroke: A Literature Review.

Right-to-left shunt, mainly due to patent foramen ovale (PFO), is likely responsible for ≈5% of all ischemic strokes and 10% of those occurring in young and middle-aged adults. Randomized clinical trials demonstrated that, in selected young and middle-aged patients with otherwise cryptogenic acute ischemic stroke and high-risk PFO, percutaneous PFO closure is more effective than antiplatelet therapy alone in preventing recurrence. However, PFO is generally a benign finding and is present in about one-quarter of the population. Therefore, in clinical practice, identifying PFOs that are likely to be pathogenetic is crucial for selecting suitable patients for PFO closure to prevent recurrent stroke and to avoid potentially harmful and costly overtreatment. Contrast transthoracic echocardiography has a relatively low sensitivity in detecting PFO, whereas transesophageal echocardiography is currently considered the gold standard for PFO detection. However, it is a relatively invasive procedure and may not always be easily feasible in the subacute setting. Contrast transcranial Doppler is a noninvasive, inexpensive, accurate tool for the detection of right-to-left shunt. We conducted a literature review on the use of contrast transcranial Doppler to detect and grade right-to-left shunt after an acute ischemic stroke and present a clinical workflow proposal for young and middle-aged patients.

Baseline Stroke Risk and Efficacy of Dual-Antiplatelet Therapy: A Post Hoc Analysis of the POINT Trial.

BACKGROUND: High-risk transient ischemic attacks and minor ischemic strokes are followed by a variable risk of ischemic stroke. We aimed to determine how baseline stroke risk modified the efficacy of clopidogrel-aspirin (referred to here as dual-antiplatelet therapy [DAPT]) for transient ischemic attack and minor ischemic stroke. METHODS: We performed an unplanned secondary analysis of the POINT trial (Platelet-Oriented Inhibition in New Transient Ischemic Attack and Minor Ischemic Stroke). We first evaluated the associations of the CHA2DS2-VASc and stroke prognosis instrument II (SPI-II) scores with the risk of incident ischemic stroke and major hemorrhage (intracranial hemorrhage or major systemic hemorrhage). We then tested for heterogeneity of the relative and absolute treatment effect of DAPT relative to aspirin across low- and high-risk patient subgroups. RESULTS: A total of 4841 trial participants were included in this analysis, with 2400 participants assigned to treatment with short-term DAPT and 2430 participants to treatment with aspirin and placebo. The dichotomized SPI-II score, but not the CHA2DS2-VASc score (P=0.18), was associated with the risk of incident ischemic stroke. A high-risk SPI-II score (>3) was associated with greater risk of incident ischemic stroke (hazard ratio of incident ischemic stroke relative to low-risk SPI-II score of 1.84 [95% CI, 1.44-2.35]; P<0.001) and numerically greater risk of major hemorrhage though not meeting statistical significance (hazard ratio, 1.80 [95% CI, 0.90-3.57]; P=0.10). The relative risk reduction with DAPT was similar across SPI-II strata (Pinteraction=0.31). The absolute risk reduction for ischemic stroke with DAPT compared with aspirin was nearly 4-fold higher (2.80% versus 0.76%; number needed to treat, 31 versus 131) in the high-risk SPI-II stratum relative to the low-risk stratum. The absolute risk increase for major hemorrhage with DAPT compared with aspirin was 3-fold higher (0.84% versus 0.30%; number needed to harm, 119 versus 331) in the high-risk SPI-II stratum relative to the low-risk stratum. CONCLUSIONS: Stratification by baseline stroke risk identifies a patient subgroup that derives greater absolute benefit from treatment with DAPT. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT00991029.

Dual Antiplatelet Versus Alteplase for Early Neurologic Deterioration in Minor Stroke With Versus Without Large Vessel Occlusion: Prespecified Post Hoc Analysis of the ARAMIS Trial.

BACKGROUND: Dual antiplatelet therapy (DAPT) was noninferior to alteplase in minor nondisabling strokes in the ARAMIS trial (Antiplatelet Versus R-tPA for Acute Mild Ischemic Stroke); however, early neurological deterioration (END) associated with vessel stenosis may benefit from DAPT. We investigated whether the efficacy of DAPT was greater than alteplase in minor strokes with no large vessel occlusion (LVO). METHODS: This study was a prespecified post hoc analysis of the ARAMIS trial and included patients with responsible vessel examination in the as-treated analysis set of the ARAMIS trial who were divided into LVO group and non-LVO group. In each group, patients were further classified into DAPT and intravenous alteplase treatments. Primary outcome was END at 24 hours defined as more than or equal to 4-point National Institutes of Health Stroke Scale score increase compared with baseline, and safety outcomes were symptomatic intracerebral hemorrhage and bleeding events during study. The primary analysis was estimated with a risk difference calculated by a generalized linear model including adjusted different baseline characteristics between treatments. RESULTS: Of 723 patients from the ARAMIS trial, 480 patients were included: 36 were categorized into LVO group and 444 into non-LVO group, of whom 20 patients had END. Compared with intravenous alteplase, a lower proportion of END was found after DAPT treatment in the non-LVO group (adjusted risk difference, -4.8% [95% CI, -6.9% to -2.6%]; P<0.001), but not in the LVO group (adjusted risk difference, 2.3% [95% CI, -17.6% to 22.3%]; P=0.82). The interaction was marginally significant between groups (P=0.06). In the non-LVO group, a lower proportion of bleeding events was found after DAPT treatment than intravenous alteplase (adjusted risk difference, -6.4% [95% CI, -8.9% to -3.9%]; P<0.001). Other safety outcomes were similar between the 2 treatments. CONCLUSIONS: Among minor nondisabling acute ischemic stroke without LVO, DAPT may be superior to intravenous alteplase regarding preventing END with a better safety profile. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03661411.

Cerebrovascular Events in Patients Undergoing Transcatheter Aortic Valve Replacement: A Review.

Cerebrovascular events (CVEs) are a dreaded complication of transcatheter aortic valve replacement (TAVR). They are associated with significant mortality, morbidity, and reduced quality of life and impose a significant burden to health care systems. Although the rates of clinical stroke have reduced since the advent of TAVR, it remains an important complication, particularly as TAVR is increasingly utilized. CVE may occur at the time of the TAVR, as a direct consequence of the procedure, or may occur later, related to thrombosis of the prosthetic valve, atrial fibrillation, and other comorbidities. Imaging of the brain has revealed a high prevalence of subclinical cerebral infarcts (68%-98%) associated with the TAVR procedure. Although their clinical significance has not been fully established, clinically evident CVE ranges between 3% and 5% in patients considered at high operative risk to between 1% and 3% in low operative risk patients. Periprocedural CVEs are largely the result of embolization of the thrombus and tissue derived from the valve, vasculature, or myocardium. Cerebral embolic protection devices have been studied in multiple trials, with some evidence supporting a reduction in new cerebral lesion volume, number, and potentially disabling strokes. However, thus far, there is no robust evidence that they reduce the overall stroke rate. The number and severity of comorbidities, in particular, new-onset atrial fibrillation, are associated with CVEs. Valve thrombosis diagnosed using computed tomography as areas of hypoattenuated leaflet thickening has been identified in 10% to 15% of patients. This is a dynamic process associated with an increase in CVEs, but that resolves with anticoagulation or sometimes without it. Routine use of anticoagulation compared with a single antiplatelet agent is associated with an increased risk of bleeding, without any additional alleviation in risk of thromboembolism. Future studies to improve risk stratification could facilitate the tailoring of preventive therapies to patients at high risk of CVE, who stand to gain the most benefit.

Cilostazol versus Aspirin or Clopidogrel for Reducing Post-Stroke Aspiration Pneumonia: A Nationwide Retrospective Cohort Study.

INTRODUCTION: The association between the use of cilostazol as a post-stroke antiplatelet medication and a reduction in post-stroke pneumonia has been suggested. However, whether cilostazol has a greater preventive effect against post-stroke aspiration pneumonia (AP) than other antiplatelet medications remains unclear. Thus, this study aimed to evaluate whether cilostazol has a greater preventive effect against post-stroke AP than aspirin or clopidogrel. METHODS: Through the Japanese Diagnosis Procedure Combination database, we identified patients who were hospitalized for ischemic stroke between April 2012 and September 2019. We performed 1:1 propensity score matching between patients who received cilostazol alone at discharge and those who received aspirin or clopidogrel alone at discharge. The primary outcome was the 90-day readmission for post-stroke AP. The occurrence of recurrent ischemic stroke within 90 days was also evaluated. RESULTS: Among the 305,543 eligible patients with ischemic stroke, 65,141 (21%), 104,157 (34%), and 136,245 (45%) received cilostazol, aspirin, and clopidogrel, respectively. Propensity score matching generated 65,125 pairs. The cilostazol group had a higher proportion of 90-day post-stroke readmissions with AP than the aspirin or clopidogrel groups (1.5% vs. 1.2%, p < 0.001). The proportion of patients with recurrent ischemic stroke within 90 days was also higher in the cilostazol group (2.4% vs. 2.2%, p = 0.017). CONCLUSION: The present study suggests that cilostazol may not have a greater effect on preventing post-stroke AP within 90 days than other antiplatelet medications. Nevertheless, further randomized controlled trials with longer follow-up periods are warranted.

Preoperative aspirin and anticoagulants do not affect partial nephrectomy bleeding.

INTRODUCTION: Studies have reached mixed conclusions on the role of antiplatelet and anticoagulant agents on postoperative complications of partial nephrectomies. This study examines whether preoperative anticoagulation use affected the risk of hemorrhagic complications after partial nephrectomy. MATERIALS AND METHODS: This is a retrospective chart review of all partial nephrectomies performed between 2017 and 2022 at a single institution. For each operation, preoperative data was gathered on whether the patient was on anticoagulation, the type and dose of anticoagulation, and how many days the anticoagulation was held preoperatively. Bivariate analyses for continuous measures were performed using Student's t-tests when there were two comparison groups and ANOVA models when there were more than two comparison groups and Chi-Square tests were used for categorical variables, with Fisher's Exact being used when expected cell counts were small. RESULTS: In this study, warfarin was held for an average of 5.43 days, clopidogrel was held for an average of 6.60 days, aspirin was held for an average of 7.65 days, and direct oral anticoagulants (DOACs) were held for an average of 4.00 days. There was no significant difference in hemoglobin (Hb) change, rate of intraoperative transfusion, postoperative transfusion, bleeding complication, pseudoaneurysm rate, or additional bleeding processes between patients on prior anticoagulation therapy and those not on therapy. There was no significant difference in intraoperative or postoperative outcomes based on history of aspirin use and continuation of aspirin through the surgery. While estimated blood loss appeared statistically significant initially, this difference was accounted for by the covariates of comorbidities, RENAL score, surgical approach, and type of renorrhaphy. Overall, there was no difference in complication rate based solely on aspirin use or continuation of aspirin through surgery. CONCLUSIONS: No difference in complication rate of partial nephrectomy was determined to be solely due to prior use of anticoagulation or aspirin use alone with appropriate cessation of anticoagulation preoperatively. Overall, patients on anticoagulation are not at a higher risk of intraoperative or postoperative bleeding complications when undergoing partial nephrectomy.

The Role of Cilostazol, a Phosphodiesterase-3 Inhibitor, in the Development of Atherosclerosis and Vascular Biology: A Review with Meta-Analysis.

Atherosclerotic cardiovascular disease (ASCVD) stands as the leading global cause of mortality. Addressing this vital and pervasive condition requires a multifaceted approach, in which antiplatelet intervention plays a pivotal role, together with antihypertensive, antidiabetic, and lipid-lowering therapies. Among the antiplatelet agents available currently, cilostazol, a phosphodiesterase-3 inhibitor, offers a spectrum of pharmacological effects. These encompass vasodilation, the impediment of platelet activation and aggregation, thrombosis inhibition, limb blood flow augmentation, lipid profile enhancement through triglyceride reduction and high-density lipoprotein cholesterol elevation, and the suppression of vascular smooth muscle cell proliferation. However, the role of cilostazol has not been clearly documented in many guidelines for ASCVD. We comprehensively reviewed the cardiovascular effects of cilostazol within randomized clinical trials that compared it to control or active agents and involved individuals with previous coronary artery disease or stroke, as well as those with no previous history of such conditions. Our approach demonstrated that the administration of cilostazol effectively reduced adverse cardiovascular events, although there was less evidence regarding its impact on myocardial infarction. Most studies have consistently reported its favorable effects in reducing intermittent claudication and enhancing ambulatory capacity in patients with peripheral arterial disease. Furthermore, cilostazol has shown promise in mitigating restenosis following coronary stent implantation in patients with acute coronary syndrome. While research from more diverse regions is still needed, our findings shed light on the broader implications of cilostazol in the context of atherosclerosis and vascular biology, particularly for individuals at high risk of ASCVD.

Anticoagulation and Antiplatelet Therapy for Prevention of Venous and Arterial Thrombotic Events in Critically Ill Patients With COVID-19: COVID-PACT.

BACKGROUND: The efficacy and safety of prophylactic full-dose anticoagulation and antiplatelet therapy in critically ill COVID-19 patients remain uncertain. METHODS: COVID-PACT (Prevention of Arteriovenous Thrombotic Events in Critically-ill COVID-19 Patients Trial) was a multicenter, 2×2 factorial, open-label, randomized-controlled trial with blinded end point adjudication in intensive care unit-level patients with COVID-19. Patients were randomly assigned to a strategy of full-dose anticoagulation or standard-dose prophylactic anticoagulation. Absent an indication for antiplatelet therapy, patients were additionally randomly assigned to either clopidogrel or no antiplatelet therapy. The primary efficacy outcome was the hierarchical composite of death attributable to venous or arterial thrombosis, pulmonary embolism, clinically evident deep venous thrombosis, type 1 myocardial infarction, ischemic stroke, systemic embolic event or acute limb ischemia, or clinically silent deep venous thrombosis, through hospital discharge or 28 days. The primary efficacy analyses included an unmatched win ratio and time-to-first event analysis while patients were on treatment. The primary safety outcome was fatal or life-threatening bleeding. The secondary safety outcome was moderate to severe bleeding. Recruitment was stopped early in March 2022 (≈50% planned recruitment) because of waning intensive care unit-level COVID-19 rates. RESULTS: At 34 centers in the United States, 390 patients were randomly assigned between anticoagulation strategies and 292 between antiplatelet strategies (382 and 290 in the on-treatment analyses). At randomization, 99% of patients required advanced respiratory therapy, including 15% requiring invasive mechanical ventilation; 40% required invasive ventilation during hospitalization. Comparing anticoagulation strategies, a greater proportion of wins occurred with full-dose anticoagulation (12.3%) versus standard-dose prophylactic anticoagulation (6.4%; win ratio, 1.95 [95% CI, 1.08-3.55]; P=0.028). Results were consistent in time-to-event analysis for the primary efficacy end point (full-dose versus standard-dose incidence 19/191 [9.9%] versus 29/191 [15.2%]; hazard ratio, 0.56 [95% CI, 0.32-0.99]; P=0.046). The primary safety end point occurred in 4 (2.1%) on full dose and in 1 (0.5%) on standard dose (P=0.19); the secondary safety end point occurred in 15 (7.9%) versus 1 (0.5%; P=0.002). There was no difference in all-cause mortality (hazard ratio, 0.91 [95% CI, 0.56-1.48]; P=0.70). There were no differences in the primary efficacy or safety end points with clopidogrel versus no antiplatelet therapy. CONCLUSIONS: In critically ill patients with COVID-19, full-dose anticoagulation, but not clopidogrel, reduced thrombotic complications with an increase in bleeding, driven primarily by transfusions in hemodynamically stable patients, and no apparent excess in mortality. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT04409834.

Estimation of DAPT Study Treatment Effects in Contemporary Clinical Practice: Findings From the EXTEND-DAPT Study.

BACKGROUND: Differences in patient characteristics, changes in treatment algorithms, and advances in medical technology could each influence the applicability of older randomized trial results to contemporary clinical practice. The DAPT Study (Dual Antiplatelet Therapy) found that longer-duration DAPT decreased ischemic events at the expense of greater bleeding, but subsequent evolution in stent technology and clinical practice may attenuate the benefit of prolonged DAPT in a contemporary population. We evaluated whether the DAPT Study population is different from a contemporary population of US patients receiving percutaneous coronary intervention and estimated the treatment effect of extended-duration antiplatelet therapy after percutaneous coronary intervention in this more contemporary cohort. METHODS: We compared the characteristics of drug-eluting stent-treated patients randomly assigned in the DAPT Study to a sample of more contemporary drug-eluting stent-treated patients in the National Cardiovascular Data Registry CathPCI Registry from July 2016 to June 2017. After linking trial and registry data, we used inverse-odds of trial participation weighting to account for patient and procedural characteristics and estimated a contemporary real-world treatment effect of 30 versus 12 months of DAPT after coronary stent procedures. RESULTS: The US drug-eluting stent-treated trial cohort included 8864 DAPT Study patients, and the registry cohort included 568 540 patients. Compared with the trial population, registry patients had more comorbidities and were more likely to present with myocardial infarction and receive 2nd-generation drug-eluting stents. After reweighting trial results to represent the registry population, there was no longer a significant effect of prolonged DAPT on reducing stent thrombosis (reweighted treatment effect: -0.40 [95% CI, -0.99% to 0.15%]), major adverse cardiac and cerebrovascular events (reweighted treatment effect, -0.52 [95% CI, -2.62% to 1.03%]), or myocardial infarction (reweighted treatment effect, -0.97% [95% CI, -2.75% to 0.18%]), but the increase in bleeding with prolonged DAPT persisted (reweighted treatment effect, 2.42% [95% CI, 0.79% to 3.91%]). CONCLUSIONS: The differences between the patients and devices used in contemporary clinical practice compared with the DAPT Study were associated with the attenuation of benefits and greater harms attributable to prolonged DAPT duration. These findings limit the applicability of the average treatment effects from the DAPT Study in modern clinical practice.

Antiplatelet Agent Use After Stroke due to Intracerebral Hemorrhage.

This focused update about antiplatelet agents to reduce the high risk of major adverse cardiovascular events after stroke due to spontaneous (nontraumatic) intracerebral hemorrhage (ICH) complements earlier updates about blood pressure-lowering, lipid-lowering, and oral anticoagulation or left atrial appendage occlusion for atrial fibrillation after ICH. When used for secondary prevention in people without ICH, antiplatelet agents reduce the risk of major adverse cardiovascular event (rate ratio, 0.81 [95% CI, 0.75-0.87]) and might increase the risk of ICH (rate ratio, 1.67 [95% CI, 0.97-2.90]). Before 2019, guidance for clinical decisions about antiplatelet agent use after ICH has focused on estimating patients' predicted absolute risks and severities of ischemic and hemorrhagic major adverse cardiovascular event and applying the known effects of these drugs in people without ICH to estimate whether individual ICH survivors in clinical practice might be helped or harmed by antiplatelet agents. In 2019, the main results of the RESTART (Restart or Stop Antithrombotics Randomized Trial) randomized controlled trial including 537 survivors of ICH associated with antithrombotic drug use showed, counterintuitively, that antiplatelet agents might not increase the risk of recurrent ICH compared to antiplatelet agent avoidance over 2 years of follow-up (12/268 [4%] versus 23/268 [9%]; adjusted hazard ratio, 0.51 [95% CI, 0.25-1.03]; P=0.060). Guidelines in the United States, Canada, China, and the United Kingdom and Ireland have classified the level of evidence as B and indicated that antiplatelet agents may be considered/reasonable after ICH associated with antithrombotic agent use. Three subsequent clinical trials have recruited another 174 participants with ICH, but they will not be sufficient to determine the effects of antiplatelet therapy on all major adverse cardiovascular events reliably when pooled with RESTART. Therefore, ASPIRING (Antiplatelet Secondary Prevention International Randomized Study After Intracerebral Hemorrhage) aims to recruit 4148 ICH survivors to determine the effects of antiplatelet agents after ICH definitively overall and in subgroups.

The role of CYP2C9*2, CYP2C9*3 and VKORC1-1639 variants on the susceptibility of upper gastrointestinal bleeding: A full case-control study.

Purpose: To investigate whether interindividual variability in the CYP2C9 (*2 and *3 alleles) and VKORC1 (rs9923231) genes is associated with increased risk of upper gastrointestinal bleeding (UGIB) in users of non-steroidal anti-inflammatory drugs (NSAIDs) or low-dose aspirin (LDA). Methods: A full case-control study including 200 cases of patients diagnosed with UGIB and 706 controls was conducted in a Brazilian hospital complex. To perform an analysis of NSAIDs dose-effect, the defined daily dose (DDD) for NSAIDs was calculated in the 7-day etiologic window preceding the data index. Three categories of DDD, considering the genotypes of the genetic variants, were established: non-users of NSAIDs (DDD = 0), DDD ≤0.5, and DDD >0.5. Genetic variants and LDA or NSAIDs use synergism was estimated through Synergism Index (SI) and Relative Excess Risk Due To Interaction (RERI). Results: For DDDs of NSAIDs upward of 0.50, a risk of UGIB was identified in carriers of the *3 allele (OR: 15,650, 95% CI: 1.41-174.10) and in carriers of the variant homozygous genotype (TT) of rs9923231 (OR: 38,850, 95% CI: 2.70-556.00). In LDA users, the risk of UGIB was observed to be similar between carriers of the wild type homozygous genotype and carriers of the variant alleles for the CYP2C9 and VKORC1 genes. No synergism was identified. Conclusion: Our findings suggest an increased risk of UGIB in carriers of the variant allele of rs9923231 and in carriers of the *3 allele associated with doses of NSAIDs greater than 0.5. Hence, the assessment of these variants might reduce the incidence of NSAIDs-related UGIB and contribute to the safety of the NSAIDs user.

Add-On Prostaglandin E1 in Venovenous Extracorporeal Membrane Oxygenation: A Randomized, Double-Blind, Placebo-controlled Pilot Trial.

Rationale: Prostaglandin E1 (alprostadil; PGE1), in addition to low-dose unfractionated heparin, increases the biocompatibility of extracorporeal systems and enhances the efficacy of artificial organs without increasing bleeding risk. Objectives: We investigated the safety and efficacy of PGE1 in adults receiving venovenous extracorporeal membrane oxygenation (ECMO). Methods: This study was a randomized, double-blind, placebo-controlled phase II pilot trial at two medical intensive care units at the Medical University of Vienna, Austria. Adults with venovenous ECMO were randomly assigned to receive an intravenous infusion of 5 ng/kg/min PGE1 or placebo (0.9% saline) in addition to standard anticoagulation with unfractionated heparin. Measurements and Main Results: The primary outcome was the rate of transfused packed red blood cells per ECMO day. Secondary outcomes were the incidence of and time to clinically overt bleeding and thromboembolic events. A post hoc subgroup analysis included only patients with coronavirus disease (COVID-19). Between September 2016 and April 2021, of 133 screened patients, 50 patients were randomized, of whom 48 received the assigned study medication (24 per group). The transfusion rate was similar between groups (0.41 vs. 0.39; P = 0.733). PGE1 was associated with fewer thromboembolic events (7 vs. 16; P = 0.020) and longer thromboembolism-free time (hazard ratio [HR], 0.302; P = 0.01), fewer clinically overt bleeding events (2 vs. 11; P = 0.017), and longer bleeding-free time (HR, 0.213; P = 0.047). In patients with COVID-19 (n = 25), the HRs for clinically overt bleeding and thromboembolism were 0.276 (95% confidence interval, 0.035-2.186) and 0.521 (95% confidence interval, 0.149-1.825), respectively. Conclusions: Add-on treatment with PGE1 was safe but did not meet the primary endpoint of reducing the rate of red blood cell transfusions in patients receiving venovenous ECMO. Larger studies need to evaluate the safety and efficacy of additional PGE1 in ECMO. Clinical trial registered with EudraCT (2015-005014-30) and www.clinicaltrials.gov (NCT02895373).

Antithrombotic Management in Adult Kidney Transplantation: A European Survey Study.

In kidney transplantation (KTx), renal graft thrombosis (RGT) is one of the main reasons for early graft loss. Although evidence-based guidance on prevention of RGT is lacking, thromboprophylaxis is widely used. The aim of this survey was to obtain a European view of the different thromboprophylactic strategies applied in KTx. An online 22-question survey, addressed to KTx professionals, was distributed by email and via platforms of the European Society for Organ Transplantation. Seventy-five responses (21 countries, 51 centers) were received: 75% had over 10 years' clinical experience, 64% were surgeons, 29% nephrologists, and 4% urologists. A written antithrombotic management protocol was available in 75% of centers. In 8 (16%) centers, respondents contradicted each other regarding the availability of a written protocol. Thromboprophylaxis is preferred by 78% of respondents, independent of existing antithrombotic management protocols. Ninety-two percent of respondents indicated that an anticipated bleeding risk is the main reason to discontinue chronic antithrombotic therapy preoperatively. Intraoperatively, 32% of respondents administer unfractionated heparin (400-10,000 international units with a median of 5,000) in selected cases. Despite an overall preference for perioperative thromboprophylaxis in KTx, there is a high variation within Europe regarding type, timing, and dosage, most likely due to the paucity of high-quality studies. Further research is warranted in order to develop better guidelines.

Subdural hygroma and hemorrhagic conversion after microsurgical clipping for unruptured intracranial aneurysm.

BACKGROUND: Chronic subdural hematoma (cSDH) is a unique hemorrhagic complication associated with microsurgical clipping. We aimed to investigate the risk factors of subdural hygroma (SDG) formation and its hemorrhagic conversion to cSDH. METHODS: We reviewed the medical records of 229 patients who underwent microsurgical clipping for unruptured intracranial aneurysms (UIA) from 2016 to 2019. Risk factors for SDG and cSDH formation were analyzed. RESULTS: Male sex, age ≥ 60 years, higher degree of arachnoid dissection, severe brain atrophy, and a large volume of subdural fluid collection (SFC) before discharge were independent risk factors for SDG formation. The risk factors for hemorrhagic conversion from SDG were continuous use or early resumption of antiplatelet drugs (odds ratio (OR): 15.367, 95% CI: 1.172-201.402) and a larger volume of SFC before discharge (OR: 0.932, 95% CI: 0.886-0.980). In the early resumption group, antiplatelet drug was resumed at a mean duration of 7.48 days postoperatively, and hemorrhagic conversion was detected earlier than that in the late resumption or no-use groups (4.09 vs. 7.18 weeks, P = 0.046). Following the receiver operating characteristic analysis, the SFC cutoff volume for hemorrhagic conversion was determined to be 23.55 mL. CONCLUSION: These findings can assist clinicians in identifying patients at a high risk of SDG and cSDH formation. Antiplatelet resumption and its timing should be determined with consideration of the risk of cSDH formation as well as individual medical conditions.

Limited benefit of systematic head CT for mild traumatic brain injury in patients under antithrombotic therapy.

BACKGROUND AND PURPOSE: Mild traumatic brain injury (mTBI) in patients on antiplatelet (AP), anticoagulant (AC) or direct oral anticoagulant (DOAC) medication has become a systematic indication for head CT. However, the over-risk and impact of the intracranial hemorrhages (IH) detected with CT in this population remain unclear and need to be assessed. MATERIALS AND METHODS: We prospectively assessed head CTs performed in adults taking AP/AC/DOAC referred after a mTBI to our Emergency Departments between September 2016 and January 2018. Frequency, type and severity of IH were described and frequency was analyzed as a function of treatment. RESULTS: 840 patients were prospectively included. 58.9% were treated with AP, 23.7% with AC, 11.7% with DOAC and 5.7% with a combination of antithrombotic agents. The rate of IH detected with head CT was 5.8% (n...=...49), of which 81.6% (n...=...40) and 18.4% (n...=...9) with minor and intermediate severity respectively. No patient required surgical care and no death occurred. No statistically significant difference was found in treatment distribution between patients with or without IH (p...=...0.98). Among the patients who discontinued their antithrombotic treatment after mTBI, three experienced thrombotic events during the hospitalization. CONCLUSIONS: Our results showed a low frequency and severity of IH in mTBI patients indifferently treated with AP, AC or DOAC, without secondary neurological deterioration, death or need of surgical care. Our study suggests the limited benefit of systematic CT head scan as a standard practice for the management of mTBI patients under antithrombotic therapy.

Dual Antiplatelet Therapy Plus Argatroban Prevents Early Neurological Deterioration in Branch Atherosclerosis Disease.

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Management of combined oral antithrombotic therapy by an antithrombotic stewardship program: A prospective study.

AIMS: Antithrombotic management initiatives could prevent inappropriate prescribing and improve patient outcomes especially in patients on combined antithrombotic therapy. To investigate this, a multidisciplinary antithrombotic stewardship program (ASP) was implemented in our hospital. The primary aim of this study was to determine the efficacy of this ASP by assessing the number of patients on combined antithrombotic therapy for whom one or more interventions were needed. METHODS: A prospective cohort study in a large teaching hospital was conducted. Hospitalized patients were included who received combined antithrombotic therapy in which an oral anticoagulant was combined with one (double therapy) or two (triple therapy) platelet aggregation inhibitors. The ASP proactively evaluated the appropriateness of this combined antithrombotic therapy. If needed, ASP improved the concerned therapy. Each improvement measurement recommended by the ASP was counted as one intervention. RESULTS: A total of 460 patients were included over a period of 12 months. Of these, 251 (54.6%) patients required at least one intervention from the ASP. The most common interventions were: (1) to define and document the maximum duration of the combined antithrombotic therapy needed instead of lifetime use of the combination (65.5%), (2) to discontinue antithrombotic therapy as the proper indication was lacking (19.4%), and (3) to adjust the dosage (8.1%). CONCLUSION: An intervention was needed in more than half of the patients on combined antithrombotic therapy. Implementation of a dedicated ASP evaluating combined antithrombotic therapy improves the use and safety of antithrombotic medication.